ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown cause that affects over 128,000 people in the United States. Median survival from diagnosis is 2-3 yrs, worse than many cancers. Irreversible fibrosis in IPF is classically thought to be the end result of abnormal signaling pathways involving alveolar epithelial cells and interstitial fibroblasts. While the role of the immune system in IPF pathogenesis remains controversial, a recent study has found that T cell specific gene expression predicts outcomes in IPF patients, thereby implicating an underlying change in T cells in patients with actively progressive disease. T cells can be divided into distinct functional subsets based on their cytokine production. As such, the changes in IPF T cell gene expression could reflect quantitative and/or qualitative changes in these subsets. Understanding the distinct subsets of T cells present in the lungs of IPF patients may explain why the variability of disease course exists as well as identify potential novel therapeutic targets. In this application, we present exciting preliminary data suggesting that striking alterations in CD4 T cell phenotypes exist within IPF lung tissue and lung draining lymph nodes (LLN) and that these alterations correlate with disease progression. We have compared CD4 T cells from explanted lung tissue and LLN from 9 subjects with IPF who underwent lung transplantation to T cells from 13 age and gender matched donor lungs and LLN that were not suitable for transplant (generous donation from Gift of Hope Regional Organ Bank of Illinois; GOH/ROBI). Using these samples, we have found that chemokine receptor expression on CD4 T cells from IPF patients differ dramatically from GOG/ROBI donor lungs. In the blood, chemokine receptors have been used to identify functionally distinct CD4 T cell subsets. Whether chemokine receptors designate specific CD4 T cell subsets in respiratory tissues is unknown and is a major objective of this application. Thus, our central hypothesis is that CD4 T cell subsets are functionally altered during IPF pathogenesis resulting in changes in their cytokine patterns within the blood, lung and LLN. The long-term goal of these studies is to elucidate the altered T cell immune response in patients with IPF, how this response changes over time, and whether it is associated with declining lung function. In this study, we propose the to elucidate if chemokine receptor expression determines functionally different CD4 subsets within the lungs and LLN in patients with IPF, and to determine how CD4 T cell subsets and T cell cytokines in the blood of a cohort of patients with IPF change over time. Completion of these studies will provide essential knowledge about the extent of these differences and the potential mechanisms by which these differences contribute to IPF pathology. Whether altered T cells are a response to fibrosis or contributing to fibrosis, understanding the location-based differences in cellular compositions, and changes in peripheral T cell cytokines over time, will provide insight into the role of key T cell subsets in IPF progression.